Guanylurea salts of penicillin



Patented Mar. 10, 1953 UNITED STATES PATENT? OFFICE assignors to American CyanamidiCompany New .York,.N.)Y., .a corporationpf Maine No-.llrawing'. Application January 24, 1952,

Serial :No.

' 8 Claims..- (01.

Our. .invention -.:.relates ;to :a renew-a series ..1of-;: penicillin; derivatives, and :their 1 preparation; jv which are comparatively water insoluble. organic penicillin salts of such characteristics that the penicillin is comparatively insoluble; and in 0 many ofwhich the penicillin is therapeutically available-as such, and the saltis non-toxic; More particularly one'aspect of theinvention relates to salts of penicillin which are slightly soluble so that' wheninj ected' forpenicillin therapy the penicillin is made'availa'ble'to the subject overa prolongedperiod'whereby a therapeutically effective penicillin blood level is maintained for a longerperiod than would be possible by the use of penicillin as-an alkali metal salt; =The range of solubility ofour new saltsis such that the bloodlevel and duration of'therapeutic eifectiveness may be controlled'toa large'extent by selecting a particular one of our salts or a mixture thereof; the variation in solubilities being such :3 that the time'may be varied over a wide range in accordance-with theusers requirements. This application is a continuation in-part of Serial Number 108,238; filed August"2,'1949, entitled Slightly Soluble Penicillin Derivatives and Methods "of Making theSame, now abandoned in favor of the presentapplication.

As. an additional; advantage;. ithe'se salts may be formed toaidin the separation or purification of penicillinin its. manufacturexand isolation; and for:such purposes the salt selectedmay be comparatively toxic, if the toxicradicals are re-' moved or their ;toXicity neutralized before the therapeutic usexuf the penicillin. It hasheen found" that the non-toxic compounds of this in- 35 vention may'readily'be used for the injection of patients with such a quantity; of a penicillinj salt that a therapeuticallyuseful" concentration of penicillin may be maintained inthe. blood level ;I of thelnormal patient .for .a period. of .over 96' hours; so that inpmanynconditions.for which, penicillin therapy is indicated, particularlyicer-r. tain venereal diseases, .a single. injection is sufv-g ficient for an. adequate course of treatment.

Also, oursalts exhibit .remarkablelstabilit asna compared with other .forms .of.penicillin, such as the alkali metalsalts. lAccordingly, our salts. make valuable additives forifeedstuffs for poultry, animals or, other organismslwhether used singly or in-combination. Theconventionalforms of 50 penicillin, such asathe alkali metallsalts ofrpenirl. cillin, aretoo. sensitiveto moisture tomake satis- 1 factory. additivesifor "feedst'uffs.

The 1 compQsition eofrthis-v invention .r hasas an: .essentialrelement. thereof the reactionproduct of .5

zoo-239.111. v1

penicillin" or one.of its'salts with a guanylnreaggr or a salt of. .a' .guanylurea, such assan acidlsalt thereof, therebypfoiming. a guanylurea'rsaltiof penicillin. 1 These salts are slightly soluble,;:-c-and;; those selected ior:therapeutic use are non-toxia; The solubility. 0f. ;.the penicillin ...G salts-loft guanylurea itselfpis "1.31% in water at'roomfitemperature Thesalts,sinlxwhich theresisia suban stituent present on; the'guanylurea nucleus-aret-r in generalless soluble For example, .benzoyl+..- guanylurea' 'pellicllllllfiG has a :solubihty ioi 0.0846% in water "at room temperaturemThesaltSm.

of the other penicillins" are comparable;

More. particularly ourl invention. includes. the.

particularly usefulfisalts of penicillin such as penicillin G, F,X,or-other penici1lin,'.with;abasic compoundfrom wx the' group consisting of guanylurea and compounds containingaa guanylr urea nucleusion" whiclrthere is present: at least one of.v theiollowing radicals: nalk'yl' including; N-N link alkylene with from 3 to 5 :carbon atoms, alkenyl, .alkynyl,..cycloalkyl,.-, monocyclic aryl, polycyclic aryl, carbamyl, monocyclic aroyl,

5-memberedimonocyclic.heterocyclic radicals and G-membered W monocyclic/ heterocyclicsz:radicalsc';

with nitrogen, sulfur. and oxygen. .hetero atoms,

includingrsuchradicals on thealiphatic portions. 1 of which; are... present ,groups. such :as.v hydroxy, 1i

alkoxy, aryl and :nitrile groups -sand 1on-=the aromatic"; portions....of :which are; present; groups such as alkyl, aryl, halogen, nitro, alkoXy, aryloxy, nitrile, hydroXy and carbethoxy groups.

These materials are 'soluble to such an extentthat when injectedgi nto. the subject :.the:.penici1=1:

lin is stored-as-a deposit but released to thez:hlood;-

stream in a therapeutically efiective:iormxatasnchgi a rate as :tamaintain: a certain blood 'level'but not at a sufficientrate.=soathat-the penicillin activity .is dissipated over an undesirably short periods. :The level and the duration. may-Joe; con-. trolled by theselection of a particularguanylureacv- Among the l-guanylureas many compounds .lcone taining the guanylurea nucleus besides guanylfl urea itself are effective, Among such are the alkyl' guanylureas suchnaswmethyl, butyl octyl or dodecyl guanylurea penicillin; the cycloalkyl cillin and di-para-chlorophenylguanylureaxlper-11+a cillin, and phenylguanylurea penicillimgcarbams..1 ylguanylureapepicillin; which may' be 'regard'ed as' r the acyl derivativelofqcarbamic acid';.:ancl.multi;--

substituted guanylureas in which the substituents may even be joined, as for example, Ni-pentamethylene guanylurea penicillin. The solubilities vary but are within the useful ranges. The field of suitable guanylureas is limited more by availability than by other technical considerations; the guanylureas which may be conveniently prepared all appear to be suitable for forming comparatively insoluble salts and the non-toxic guanylureas appear to be satisfactory for direct injection into patients.

Many guanylureas are known which will form salts with penicillin. As illustrative, but in no way limiting, examples of certain such guanylureas are:

Aliphatic guanylureas Aromatic guanylureas Phenylg ianylurea Iodophenylguanylurea Chlorophenvlguanylurea Nitrophenylguanx lurea Tolylguanylurea Carbethoxyphenylguanyl- Xvlylzuanylurea urea Erhylphenylguanylurea Aminoplienylguanylurea Isoprcpylphenylguanylurea Meta hydroxyphenylgua- Butrlnhenylguanylurea nylurea Isobutylphenyguanvlurea Para hydroxyphenylgua: Methoxyphenvlzuanvlurea nylurea Ethoxynhenylguanrlurea Acetaminophenylguanylurea Bromophenylguanylurea Cyanophenylguanylurea Acylguanylureas Acetylgua nylurea Pelargcnylguanylurea Propionylguanvlurea Caprylguanylurea Butyrylgunnylurea Lauryleuanylurea Valeryleuanylurea Myrlsiylzuanylurea Caprovlguanylurea Palmitvlguanylurea Enanthylguanylurea Ste-a rylguanylurae Caprylylguanylurea Carbamylguanylurea Aroylguanylureas Benzoyle'uanylurea Methoxvb nzovlguanylurea Naphfhoylguanylurea Ethoxybenzoylzuanylurea Methylbenzoylguanylurea Chlorobenzoyleuanvlurea Bromobenznylguanylurea Acetaminobenzoylguanylurea Benzenesulfonylguanylurea Io lobenzoylguanvlurea Anisic guanylurea Nitrobenzoylguanylurea Heterocyclzc guanylureas Triazolvlzuanylurea. Pyridylguanylurea Thiazolvlzuanylurea Pyrrolylguanylurea Imidazolylzuanylurea Furfurylguanylurea Thiazclirlvleuanylurea Pvranylguanylurea Im idaz lidvleuanylurea Thenylguanvlurea Pyrazoli ylguanvlurea In olvlguunylurea Pyraznlylauanvlurea Quinnlyltzuanylurea. Furylguanylurea Isoouln olylguanylurea Thien l ,zuanvlurea Carbuzolvlguanylurea Pyrrvleun nvlurea A cridvl'ruanvlurea Pyrrolir'ivlmmnylurea Xanthvlzunnylurea Mornholinvlznanylurea Pyrimidvlcuanylurea Then ovla'uan vlurea Quinoxalvlguanvlurea Furoylguanylurea Piperidylguanylurea M ired aZkyl-aryl guanylureas N phenyl N methylguanyL urea N phenyl N ethylguanylurea N phenyl N propylguanylurea N phenyl N butylguanylurea N phenyl N hexylguanylurea N phenyl N cyclohexylgua- N chlorophenyl N methylguanylurea N chlorophenyl N butylguanylurea N chlorophenyl N cyclohexylg lmnylurea Nxylyl ethylguanylurea N tolyl N isopropylguanyk urea N hydroxyphenyl N ethylguanylurea nylureu Preparation The penicillin derivatives may be prepared by the use of a free guanylurea base and free penicillin but inasmuch as penicillin is normally more conveniently commercially available as a salt such as for example the sodium salt of penicillin G, potassium salt of penicillin G or of penicillin F, silver salts of the various penicillins, the amine salts such as triethylamine salt, etc., and as the guanylureas are generally more conveniently available as an acid salt such as the hydrochloride, the sulfate, the nitrate, the phosphate, the acetate, etc., it is normally more convenient to use the acid salts of a guanylurea and a basic salt of a penicillin than otherwise. The reaction may be conveniently carried out in water, methanol, ethanol, propanol, butanol, Z-ethoxyethanol, 2- methoxyethanol, other alkoxy ethanols, other alcohols, dioxane, acetone, methylethyl ketone, methylisobutyl ketone, mixtures of two or more of these solvents or other common solvents. Because water is the cheapest, it is most conveniently used.

For most purposes penicillin G is selected as the form of penicillin of choice because penicillin G has met with greater acceptance by the medical profession than the other penicillins, but it is to be understood that if for a particular treatment some other penicillin or a mixture of penicillins is desired, these may be used. For use therapeutically, it is normally desired that the inert materials injected be held to a minimum and accordingly guanylureas of a lower molecular weight are more desirable so as to not overburden the body with an unduly large weight ratio of inert material. For therapeutic use the penicillin salt of a particular guanylurea is most frequently formed with an inert salt as for example sodium chloride, resulting from the salts used in its formation. These inert salts may be removed but are frequently found to be desirable as they in crease the salinity of the material. Normally the crystal habit in which the crystals are formed is suitable for injection but in some instances recrystallization in suitable solvents may be desired. For purposes of injection the material may be suspended in a suitable medium such as distilled water, normal saline, 20% propylene glycol or other commonly used aqueous diluents or an oil such as peanut oil, sesame oil, cottonseed oil or other assimilable tri-glyceride together, in every case, with such stabilizing agents, bufiers, thixatherefrom into the subject. T i

In addition to a guanylurea penicillin'salt or 'a" .s. mixture thereof ,-it is frequently desirableto have a sodium, potassium'or calcium "salto'f penicillin additionally presents'o as to "insure "a high initial blood level of penicillinlinitheltsubject as well as a prolonged bloodalevel, resultinglfrom a guanylurea penicillin.

Guanylurea itselt has the: formula Nnr'oenncnnfi NH 0 l" For ..purposes gof :nomenclature;- the compoundsas; of this invention can'abeiconsideredeas:penicillin1;. salts *ofzzithe guanyl "derivatives of 1: .ureaz-r By. analogyszto :thexnomencla turemf ztherzamidineide rivatives, the nitrogen of the NHz-igroup is designated N, and thenitrogenof the :NH group as N. All the derivatives in the specific examples and claimshave the:substituents on the nitrogenof .the Nl-Iagrdup, ..Some confusion in terminology exists withrespect to theterm ,aryLl. For purposesoi .thepresentclaims,faryli is used to refer to hydrocarbon radica1s.....

As illustrations. of v .,certain .of thepsuitable guanylurea salts, .but .not .by-way. of limitation, there .a-rev herewith .set, forthrcertain specificlexe amples.

The various .-guanylureas..themselves. may. be... t. prepared in .various. fashions. .A .cOnVenient. method. of preparation .is .by. starting with the acid addition .salt; .of i anwamineuand a metallicll salt of dicyanimide and reacting.thelmaterials; in substantially molar proportions to form substituted cyanoguanidine;- Certain improvements in the method ofeformationare'set forth in a 40 patent of Bryan C. Redmon and Daniel E. Nagy, 2,455,807, December '7, 1948,.entitled Preparation of Substituted Cyan0guanidine.. The thus formed substituted cyanoguanidine may then be reacted with water in the presence of a strong mineral acid to form a corresponding guanylureasi Certain of the acyl guanylureas which are :suit.--

able. for the purposerof our inventiongare de-;

scribed in detail in a. paten-tto Donald W.- Kaiser T" and Jacki. Thurston,-2,397,667,- April. 2, .1946, e

entitled .fAcyl-Guanylureas and Their Prepara-a- 1 tioni As a specificexample to illustrate. the general method, n-octylguanylurea"neutral sulfate zdihyajs drate,

ts t

maybeprepared fromn-octyldicyandiamide pre-' '60 pared from octylaminesulfate andxsodiu mdi-i cyanimide; To 100-"grams-' of :the 'octyl'dicyandi-= amide is added 200 milliliters of concentrated'hydrochloric acid and '75 milliliters of dioxane. The mixture is heated on a steam bath for an hour, then distilled under'reducedpressure to remove the dioxane. To the residue is added 200 milliliters of water, and then 1501 grams of sodium sulfate. ihe n-octylguanylurea neutral sulfate separates as an oil which later solidifies,'the mixture is filtered, thev solidvslurried in..water, again... filtered; andis dried in a desiccator. Ihef'gummy product is extracted withflacetone, leaving 65.; grams of the'acetoneinsoluble material whichls recrystallized" fronr'a mixture of i 1400 mi1liliters,..75

. water 6 if of water. and... 4D0jml11111trsf -ethanol thereby. yicldili'git he einydrate r ctctrlsuanylure m a sulfate; melting .pqintallOf TC. "Isdftensl;

EXAMPLE]. l;

Gutmylur'ea 'penetlliwbt :3

25.9 grams of crystallineisodium pencillin G is dissolved in sopmillilitersof .distilled. Water and added slowly to a solution of 10g'rams of guanylurea hydrochloride'in -20"milliliters-- of distilled at room temperature. After approximately. 1 3/3 ..of.ithe,spenicillinasolution. is added. crystals for guanylureaipenicill-in.hegin .to appear. Theiremainingspenicillinsolution. is then. added dropwiseand thesuspensicncooled to and stirred 20 at 119C. Ifor'A hours to permit substantially come pleteprecipitation of .the.desirediprod-uct. ..There... is thereby obtained; 30.2..Jgramscf: guanylurea'. penicillin, with a melting -point .of- 151-1529.

Which-lhas av theoretical analysis of 1360-. units of.

penicillin activity per. milligram and which onv laboratory analysis is foundto possess 1357 units... per milligram. Theoretically'the material possesses an analysis of :a:

Percent "Carbon 49.54

Hydrogen 5.53 Nitrogen 19.26

For one specific run an analysis showed-the prod- .uct to'contain:

Percent;.... Carbon "1'. s 48.891 Hydrogen 5.58? Nitrogen 1 19.05

The-product .is soluble in wateretotthe:.1extent:of: 1.313% M25305;

Cycloheccylguanylurea.-p.enici1li1t NH'T.O"?NH*-C'- HE-Ff t m t 5' 5 parts of cycloheirylguanylurea hydrochloride is dissolved in milliliterszof distilled Water and thereto is added a so1ution..of.7...5 parts of crystalline sodium penicillinG dissolved in 100 parts of distilled Water. Aheavy crystalline precipitate of cyclohexylguanylurea.spenicillin 5 is thereby formed. .The material .is allowed to cool for about 4 hours at 4 C. and the precipitate collected on a sintered glass filter, :washed with water; andidriedzinivacnoioverphosphorusCpent+ oxide. -.'I'lie;.materia'l has 12a theoretical zicontenti 1 r of 1,100 ,units .ner vmilligram and-on:analysis .was; fcundi-to :containzlfi amitsiper :millig-ram :1 The; materi sis solu-bleto the eXtentr.of:-0.354%-"in n-octylgrianylurea pe1tic'illii1i csfiflqNH lc' x 7 parts of n-octylguanylurea'. sulfate dihydrate is dissolved-inwater by Warming onthe steam bath. To theeclears-solutioniithus--obtainable is carefully added a solutionecontaining 7 parts of crystalline sodium penicillin G in 50 parts of water; a heavy crystalline precipitate of n-octylguanylure'a being formed. This is collected on a sintered glass funnel, washed, and dried in vacuo. There is obtained a product soluble to the extent of about 0.112% in water with an actual analysis of 1023 units per milligram as contrasted with the theoretical analysis of 1080 units per milligram.

EXAMPLE 4 Dodecylguanylurea penicillin C 1zHz5NHCNH('J-NH2 NH i 3.9 grams of dodecylguanylurea hydrochloride is dissolved in a minimum of water and there is added thereto 45 milliliters of an aqueous solution containing a theoretical proportion of crystalline sodium penicillin G. A heavy white crystalline precipitate is formed which may be thinned with an additional '75 milliliters of water if desired to render filtration more convenient. The crystals are collected on a sintered glass funnel, washed with water, and dried. The product is soluble to the extent of 0.024% in water.

EXAMPLE 5 Benzoylguanylurea penicillin 5 parts of benzoylguanylurea hydrochloride is dissolved in 100 parts of distilled water and thereto added a solution of 6.5 parts of crystalline sodium penicillin G in 50 parts of distilled water. A heavy crystalline precipitate of benzoylguanylurea penicillin G is thereby formed; which may be collected on a glass filter, washed with distilled water, and dried in vacuo. The product is soluble to the extent of 0.084.673 in water and has an actual analysis of 916 units per milligram compared to a theoretical 1096 units per milligram. Whereas this material is insoluble its rate of hydrolysis is relatively high so that it is more available than would appear from the solubility characteristics alone.

EXAMPLE 6 p-Chlorophenylguanylurea penicillin -Nn-c-Nn-(";-Nrn 1 IIQH c1 p-Chlorophenylguanylurea hydrochloride was obtained by the controlled acid hydrolysis of l-para-chlorophenyl-3-cyanoguanidine. To 2.5 grams of this product suspended in 75 milliliters of distilled water there was added 3.5 grams of penicillin G dissolved in 25 milliliters of distilled water. The suspension was stirred for two hours, the precipitate collected, washed with water, and dried in vacuo. The material was found to have an actual analysis of 1019 units per milligram; the theoretical being 1088.

To a. theoretical proportion of carbamylguanylurea hydrochloride dissolved in parts of distilled water is added a solution of 6.5 parts of crystalline sodium penicillin G and 50 parts distilled water. A crystalline precipitate will be thereby formed which upon being collected on a suitable filter, washed, and dried, will be found to be carbamylguanylurea penicillin.

EXAMPLE 8 Guanylurea penicillin To 50 parts of a free penicillin dissolved in 100 parts of ethanol is added a solution of a theoretical quantity of guanylurea, the free base. in 200 parts of distilled water. The two components may be mixed together, then cooled, and the crystals of guanylurea penicillin separated therefrom. The thus formed guanylurea penicillin will be found to be identical with that from Example 1.

EXAMPLE 9 Purification of penicillin EXAMPLE 10 Beta-phenylethylguanylurea penicillin 8.0 grams of beta-phenylethylguanylurea nitrate dissolved in 100 milliliters of 50% aqueous ethyl alcohol are added slowly to a solution of 17 grams potassium penicillin G in 100 milliliters 50% alcohol. After approximately 15 seconds, crystals of the desired penicillin salt begin to appear. The suspension was cooled to 4 C. for one hour to permit substantially complete precipitation of the desired product. There is thereby obtained 16 grams of beta-phenylethyl guanylurea penicillin with a melting point of 142-143 C. which has a theoretical analysis of 1100 units of penicillin activity per milligram and which on laboratory analysis is found to possess 1050 units per milligram. The product is soluble in water to the extent of 0.05% at 25 C., and is sufiiciently stable to be an excellent additive for poultry feed.

EXAMPLE l1 Pam-methoazyphenylguanylurea penicillin l CHr-O NH O 5.0 grams of para-methoxyphenylguanylurea hydrochloride are dissolved in 100 milliliters of 50% alcohol and added to a solution of 8.0 grams of sodium penicillin G in 50 milliliters alcohol. On cooling to 4 C. a heavy crystalline precipitate of para-methoxyphenylguanylurea penicillin forms which is collected and dried. The material has an aqueous solubility of about 0.2% and with an actual analysis of 1050 units per milligram as compared with a theoretical analysis of 1090 units per milligram.

EXAMPLE 12 Beta-phenylisopropylguanylurea penicillin EXAMPLE 13 Para-tolylguanylurea penicillin 6.0 grams of para-tolylguanylurea hydrochloride are dissolved in 60 milliliters of 50% ethyl alcohol and added slowly to a solution of 10.8 grams of potassium penicillin G in 60 milliliters of 50% ethyl alcohol at 50 C. Crystallization of the desired para-tolylguanylurea salt of penicillin begins almost immediately. After one hour at 4 C. the compound is collected, Washed with Water and dried. The material has a theoretical content of 1130 units per milligram and on analysis is found to contain 1070 units per milligram. The material has an aqueous solubility of approximately 0.2%.

EXAMPLE 14 Phenylguanylurea penicillin 5.0 grams of phenylguanylurea hydrochloride are dissolved in 50 milliliters of 40% ethanol and added slowly to a solution of 9 grams of sodium penicillin G dissolved in 40% ethanol; a heavy crystalline precipitate of phenylguanylurea penicillin being formed. This material is collected in a sintered glass funnel, washed with water and dried in vacuo. The product is soluble to the extent of approximately 0.2% in water with an actual analysis of 1049 units per milligram as compared to a theoretical analysis of 1159 units per milligram.

EXAMPLE 15 Dibutylguanylurea penicillin 0.01 mole of dibutylguanylurea nitrate in 100 milliliters of ethyl alcohol is mixed with 0.01 mole of sodium penicillin dissolved in 100 milliliters of ethyl alcohol. Sodium nitrate which 10 forms is separated by filtration. The dibutylguanylurea penicillin is precipitated from the solution by the addition of 600 milliliters of ethyl ether. A white, amorphous, therapeutically active powder is obtained which may be separated by filtration.

EXAMPLE 16 Thiazolylguanylnrea penicillin 0.02 mole of thiazolylguanylurea nitrate in 200 milliliters of propanol is reacted With 0.02 mole of potassium penicillin dissolved in 200 milliliters of butanol. The potassium nitrate formed is separated and the thiazolylguanylurea penicillin salt formed in the reaction is precipitated by the addition of 1500 milliliters of ethyl ether. The precipitate is filtered off, washed with ethyl ether, and thereby is obtained a White, amorphous, therapeutically active powder.

EXAMPLE 17 N-phenyl-N-methylguanylurea penicillin 0.01 mole of N-phenyl-N-methylguanylurea nitrate dissolved in milliliters of 2-ethoxyethanol is reacted with 0.01 mole of ammonium penicillin dissolved in 100 milliliters of 2-ethoxyethanol. The thus formed N-phenyl-N-methylguanylurea penicillin salt is precipitated by the addition of 800 milliliters of ether and is separated from the solvents by filtration. The salt is Washed, first with ether, then with water, and thereby is obtained a White, amorphous, therapeutically active powder.

Having thus set forth by description and example certain aspects thereof, as our invention we claim:

1. The salt of penicillin and a compound selected from the group consisting of guanylurea, N-alkylguanylurea, N,N dialkylguanylurea, N- cycloalkylguanylurea, N-monocyclic arylguanylurea, N-monocyclic haloaryl guanylurea, N -aralkylguanylurea, N-monocyclic lower alkoxyarylguanylurea, N -monocyclic lower alkaryl guanylurea, N-alkyi-N-aryl-guanyiurea, la gua1iylurea, N-carbamyl guanylurea and N-monocyclicaroylguanylurea.

2. The salt of penicillin and N-cyclohexylguanylurea.

3. The salt of penicillin and N -octylguanylurea.

4. The salt of penicillin and N-beta-phenylethylguanylurea.

5. The salt of penicillin and N-phenylguanylurea.

6. The salt of penicillin and N-parachlorophenylguanylurea.

7. The salt of penicillin and N-alkylguanylurea.

8. 'lhe salt of penicillin and N -monocyclicarylguanylurea.

LAWRENCE BITTER. JOSEPH F. WEIDENHEIMER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,565,503 Kaplan Aug. 28, 1951 2,578,641 Cooper Dec. 11, 1951 FOREIGN PATENTS Number Country Date 471,147 Canada Jan. 30, 1951 

1. THE SALT OF PENICILLIN AND A COMPOUND SELECTED FROM THE GROUP CONSISTING OF GUANYLUREA, N-ALKYLGUANYLUREA, N,N - DIALKYGUANYLUREA, NCYCLOALKYLGUANYLUREA, N-MONOCYLIC ARYLGUANYLUREA, N-MONOCYCLIC HALORAYL GUANYLUREA, N-ARALKYLGUANYLUREA, N-MONOCYCLIC LOWER ALKOXYARYLGUANYLUREA, N-MONOCYCLI LOWER ALKARYL GUANYLUREA, N-ALKYL-N-ARYL-GUANYLUREA, N-GUANYLUREA, N-CARBAMYL GUANYLUREA AND N-MONOCYCLICAROYLGUANYLUREA. 